Skin and mucosa have always been regarded as physical barriers to the outside environment; protecting the host from noxious intruders. Recent findings have led to the realization that these barriers are not only physical; they generate potent antimicrobial peptides (APs). These ancient compounds, first described in drosophila, are now known to be important for the “innate” immune system of a eukaryotic host. Antimicrobial peptides act on a broad spectrum of pathogens. The innate immune system works in conjunction with the adaptive immune system in mammals, by permitting the host to curb, delay, or avoid microbial growth shortly after an infection. Innate responses occur in a matter of hours, well before the acquired immune system can be sufficiently mobilized.
The defensin peptides are a superfamily of peptide antibiotics with a characteristic beta-sheet structure stabilized by two to three intramolecular disulfide bonds. They are strongly cationic by virtue of their numerous arginine and lysine residues. The amphipathic and cationic characteristics are important for antibacterial activity. Defensin peptides have been isolated from a number of phagocytes from mammals including humans, and various tissue and fluid sources such as mammalian trachea, intestine, tongue, human oral gingiva, human organs, plasma and urine.
The human defensin AP family is roughly divided into two subfamilies; alpha-defensins, found in azurophilic granules of PMNs and in the granules of Paneth cells found in the base of the crypts of Lieberklühn in the small intestine, and the beta-defensins, expressed generally by epithelial cells. The alpha- and beta-defensins differ in primary sequence and in the placement of the three disulfide bonds. The signature motif for beta-defensin genes includes two exons surrounding a variably sized intron. Exon 1 encodes the signal sequence, while exon 2 encodes the propeptide and mature peptide. This motif differs from that found in alpha-defensin genes in that the latter are organized with three exons and two introns. Other differentiating features between alpha- and beta-defensins include the fact that while the former are cytotoxic to mammalian cells when released from protective granules, the latter are not.
In addition to demonstrating antibacterial and antifungal properties, beta-defensins engage the CCR6 receptor on selected immune effector cells, such as immature dendritic cells and T cells and evoke a chemokine response, thereby recruiting these cells to the site of interest.
The growing problem of resistance to conventional antibiotics and the need for new antibiotics has stimulated interest in the development of antimicrobial peptides (APs) as therapeutics for humans and other animals. Unlike conventional antibiotics, acquisition of resistance by a sensitive organism against APs is surprisingly rare and difficult to generate.
Accordingly, it would be desirable to have compositions and methods for causing cells to increase production of beta-defensins.